tbuckley/cabot-search huggingface dataset:
FGFR3 Mutational Activation Can Induce Luminal-like Papillary Bladder Tumor Formation and Favors a Male Sex Bias
Authors: Ming-Jun Shi, Jacqueline Fontugne, Aura Moreno-Vega, Xiang-Yu Meng, Clarice Groeneveld, Florent Dufour, Aurélie Kamoun, Sia Viborg Lindskrog, Luc Cabel, Clémentine Krucker, Audrey Rapinat, Claire Dunois-Larde, May-Linda Lepage, Elodie Chapeaublanc, Olivier Levrel, Victoria Dixon, Thierry Lebret, Anna Almeida, Aurélien De Reynies, Natacha Rochel, Lars Dyrskjøt, Yves Allory, François Radvanyi, Isabelle Bernard-Pierrot
Journal: European Urology (2022)

Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes.To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias.We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared.Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure.Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays.FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3-driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors.Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity.By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.
Humoral and cellular responses to the third COVID-19 BNT162b2 vaccine dose in research institute workers in Japan
Authors: Akihiko Nishikimi, Takeshi Nakagawa, Mitsuhiro Fujiwara, Ken Watanabe, Atsushi Watanabe, Ayane Komatsu, Mikako Yasuoka, Ryota Watanabe, Masahiro Naya, Hironori Oshima, Yuichi Kitagawa, Haruhiko Tokuda, Izumi Kondo, Shumpei Niida, Takashi Sakurai, Masayo Kojima, Hidenori Arai
Journal: Journal of Infection (2022)
Photonic and magnetic materials for on-demand local drug delivery
Authors: Ilaria Armenia, Carlos Cuestas Ayllón, Beatriz Torres Herrero, Francesca Bussolari, Gabriel Alfranca, Valeria Grazú, Jesús Martínez de la Fuente
Journal: Advanced Drug Delivery Reviews (2022)

Nanomedicine has been considered a promising tool for biomedical research and clinical practice in the 21st century because of the great impact nanomaterials could have on human health. The generation of new smart nanomaterials, which enable time- and space-controlled drug delivery, improve the limitations of conventional treatments, such as non-specific targeting, poor biodistribution and permeability. These smart nanomaterials can respond to internal biological stimuli (pH, enzyme expression and redox potential) and/or external stimuli (such as temperature, ultrasound, magnetic field and light) to further the precision of therapies. To this end, photonic and magnetic nanoparticles, such as gold, silver and iron oxide, have been used to increase sensitivity and responsiveness to external stimuli. In this review, we aim to report the main and most recent systems that involve photonic or magnetic nanomaterials for external stimulus-responsive drug release. The uniqueness of this review lies in highlighting the versatility of integrating these materials within different carriers. This leads to enhanced performance in terms of in vitro and in vivo efficacy, stability and toxicity. We also point out the current regulatory challenges for the translation of these systems from the bench to the bedside, as well as the yet unresolved matter regarding the standardization of these materials.
Staphylococcus lugdunensis prosthetic joint infection: A multicentric cohort study
Authors: Yannick Herry, Olivier Lesens, Gaelle Bourgeois, Mylène Maillet, Romain Bricca, Céline Cazorla, Judith Karsenty, Tomasz Chroboczek, Anissa Bouaziz, Julien Saison, Marie-Elodie Langlois, Céline Dupieux-Chabert, Tristan Ferry, Florent Valour
Journal: Journal of Infection (2022)
A complicated case of monkeypox and viral shedding characteristics
Authors: Mahir Kapmaz, Derya Salim Uymaz, Gulin Ozcan, Tayfun Barlas, Gulen Guney-Esken, Mete Manici, Şiran Keske, Mert Kuşkucu, Füsun Can, Önder Ergönül
Journal: Journal of Infection (2022)
Biophysical heterogeneity of myeloid-derived microenvironment to regulate resistance to cancer immunotherapy
Authors: Jie Zhao, Yiting Dong, Yundi Zhang, Jie Wang, Zhijie Wang
Journal: Advanced Drug Delivery Reviews (2022)

Despite the advances in immunotherapy for cancer treatment, patients still obtain limited benefits, mostly owing to unrestrained tumour self-expansion and immune evasion that exploits immunoregulatory mechanisms. Traditionally, myeloid cells have a dominantly immunosuppressive role. However, the complicated populations of the myeloid cells and their multilateral interactions with tumour/stromal/lymphoid cells and physical abnormalities in the tumour microenvironment (TME) determine their heterogeneous functions in tumour development and immune response. Tumour-associated myeloid cells (TAMCs) include monocytes, tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and granulocytes. Single-cell profiling revealed heterogeneous TAMCs composition, sub-types, and transcriptomic signatures across 15 human cancer types. We systematically reviewed the biophysical heterogeneity of TAMC composition and pro/anti-tumoral and immuno-suppressive/stimulating properties of myeloid-derived microenvironments. We also summarised comprehensive clinical strategies to overcome resistance to immunotherapy from three dimensions: targeting TAMCs, reversing physical abnormalities, utilising nanomedicines, and finally, put forward futuristic perspectives for scientific and clinical research.
A misadventure of the correlation coefficient
Authors: Dmitri A. Rusakov
Journal: Trends in Neurosciences (2022)

The correlation coefficient gauges linear association between two variables. However, interpreting its value depends on the question at hand. This article argues that relying on the correlation coefficient may be irrelevant for many neuroscience research tasks. When the experimental dataset is contextually suitable for binning-averaging, other indicators of statistical association could prove more suitable.
Rhodopsin, light-sensor of vision
Authors: Klaus Peter Hofmann, Trevor D. Lamb
Journal: Progress in Retinal and Eye Research (2022)

The light sensor of vertebrate scotopic (low-light) vision, rhodopsin, is a G-protein-coupled receptor comprising a polypeptide chain with bound chromophore, 11-cis-retinal, that exhibits remarkable physicochemical properties. This photopigment is extremely stable in the dark, yet its chromophore isomerises upon photon absorption with 70% efficiency, enabling the activation of its G-protein, transducin, with high efficiency. Rhodopsin's photochemical and biochemical activities occur over very different time-scales: the energy of retinaldehyde's excited state is stored in <1 ps in retinal-protein interactions, but it takes milliseconds for the catalytically active state to form, and many tens of minutes for the resting state to be restored. In this review, we describe the properties of rhodopsin and its role in rod phototransduction. We first introduce rhodopsin's gross structural features, its evolution, and the basic mechanisms of its activation. We then discuss light absorption and spectral sensitivity, photoreceptor electrical responses that result from the activity of individual rhodopsin molecules, and recovery of rhodopsin and the visual system from intense bleaching exposures. We then provide a detailed examination of rhodopsin's molecular structure and function, first in its dark state, and then in the active Meta states that govern its interactions with transducin, rhodopsin kinase and arrestin. While it is clear that rhodopsin's molecular properties are exquisitely honed for phototransduction, from starlight to dawn/dusk intensity levels, our understanding of how its molecular interactions determine the properties of scotopic vision remains incomplete. We describe potential future directions of research, and outline several major problems that remain to be solved.
Long-term Gastrointestinal Sequelae Following COVID-19: A Prospective Follow-up Cohort Study
Authors: Rithvik Golla, Sudheer Vuyyuru, Bhaskar Kante, Peeyush Kumar, David Mathew Thomas, Govind Makharia, Saurabh Kedia, Vineet Ahuja
Journal: Clinical Gastroenterology and Hepatology (2022)
Corrigendum to ‘Mendelian susceptibility to mycobacterial diseases: state-of-the-art’ [Clin Microbiol Infect 28(11) (2022 Nov) 2876]
Authors: Kosuke Noma, Yoko Mizoguchi, Miyuki Tsumura, Satoshi Okada
Journal: Clinical Microbiology and Infection (2022)
Randomized phase 2 trial of intravenous oncolytic virus JX-594 combined with low-dose cyclophosphamide in patients with advanced soft-tissue sarcoma
Authors: Maud Toulmonde, Sophie Cousin, Michèle Kind, Jean-Philippe Guegan, Alban Bessede, Francois Le Loarer, Raul Perret, Coralie Cantarel, Carine Bellera, Antoine Italiano
Journal: Journal of Hematology & Oncology (2022)

Abstract JX-594 is an oncolytic vaccinia virus genetically modified to replicate selectively in tumor cells. Metronomic chemotherapy has shown preclinical synergy with oncolytic viruses. We report here the results of the METROMAJX which is a randomized phase II clinical trial investigating the combination of JX-594 combined with metronomic cyclophosphamide (arm 1) or metronomic cyclophosphamide (arm 2) in patients with advanced STS. A two-stage Simon design was used. JX-594 was administered intra-venously at the dose 1.109 every 2 weeks for the first 3 injections and then every 3 weeks. Cyclophosphamide was given orally at the dose of 50 mg BID 1 week on 1 week off. The primary endpoint was the 6-month non progression rate. 20 patients were included (arm 1:15, arm 2:5). The two most frequent toxicities were grade 1 fatigue and fever and grade 2 fatigue and grade 2 lymphopenia in arms 1 and 2, respectively. In arm 1, 12 patients were assessable for the efficacy analysis. None of them were progression-free at 6 months indicating that the first stage of the Simon's design was not satisfied. One patient out 4 assessable for efficacy was progression-free at 6 months in arm 2. High throughput analysis of sequential plasma samples revealed an upregulation of protein biomarkers reflecting immune induction such as CXCL10 and soluble CD8 antigen in arm 1. Systemic treatment with JX-594 is safe in patients with advanced STS. Further investigations are needed to improve immune response to oncolytic viruses and define their therapeutic potential in patients with STS.
Handgrip strength and respiratory disease mortality: Longitudinal analyses from SHARE
Authors: R. Mey, J. Calatayud, J. Casaña, R. Torres-Castro, F. Cuenca-Martínez, L. Suso-Martí, L.L. Andersen, R. López-Bueno
Journal: Pulmonology (2022)

While the association between handgrip strength and all-cause mortality is more deeply explored, no previous studies have been specifically focused on handgrip strength and respiratory disease mortality. The purpose of the study was to investigate the association between handgrip strength and respiratory disease mortality in a large representative sample. Individuals aged 50 or over from 27 European countries and Israel participated in this longitudinal study. Data on handgrip strength and all-cause and respiratory disease mortality were retrieved from the Survey of Health, Ageing and Retirement in Europe (SHARE) waves 1, 2, 4, 5, 6 and 7. We estimated the sub hazard ratios (SHRs) for respiratory disease mortality using a Fine-Gray sub-distribution method with both time-varying exposure and covariates and mortality due to other causes as competing risk. Furthermore, we assessed dose‐response associations of handgrip strength (modelled as a continuous exposure) with respiratory disease mortality using restricted cubic splines and estimated hazard ratios (HRs). We included 60,883 men and 74,904 women with a mean age of 63.6 (SD 9.7) years at study entry. During a median (interquartile range) of 7.4 years of follow-up 565 (0.4%) participants died due to respiratory diseases. The increase of 1 single kg of handgrip strength showed a 6% incidence reduction on respiratory disease mortality (SHR, 0.94; 95%CI, 0.92-0.96) after adjusting for potential confounders. Furthermore, each kg increase of handgrip strength reduced respiratory disease mortality risk in a dose-response fashion and a significant threshold for values of 41 kg (HR, 0.49; 95%CI, 0.26-0.92) and higher was identified. Higher handgrip strength is associated with lower mortality due to respiratory disease. Intervention studies are needed to determine whether strength training in respiratory disease patients can prevent premature mortality.
SF3B1 mutations in AML are strongly associated with MECOM rearrangements and may be indicative of an MDS pre-phase
Authors: Sandra Huber, Torsten Haferlach, Manja Meggendorfer, Stephan Hutter, Gregor Hoermann, Constance Baer, Wolfgang Kern, Claudia Haferlach
Journal: Leukemia (2022)
Classification of rare pediatric myeloid neoplasia—Quo vadis?
Authors: Charlotte M. Niemeyer, Martina Rudelius, Akiko Shimamura, Christian Flotho, Henrik Hasle, Elliot Stieglitz, Brigitte Strahm, Lucy A. Godley, Olga K. Weinberg, Attilio Orazi, Katherine R. Calvo
Journal: Leukemia (2022)
Histone Lactylation Boosts Reparative Gene Activation Post–Myocardial Infarction
Authors: Naixin Wang, Weiwei Wang, Xiaoqi Wang, Ge Mang, Jianfeng Chen, Xiangyu Yan, Zhonghua Tong, Qiannan Yang, Mengdi Wang, Liangqi Chen, Ping Sun, Yupeng Yang, Jingxuan Cui, Mian Yang, Yafei Zhang, Dongni Wang, Jian Wu, Maomao Zhang, Bo Yu
Journal: Circulation Research (2022)

Background: Inflammation resolution and cardiac repair initiation after myocardial infarction (MI) require timely activation of reparative signals. Histone lactylation confers macrophage homeostatic gene expression signatures via transcriptional regulation. However, the role of histone lactylation in the repair response post-MI remains unclear. We aimed to investigate whether histone lactylation induces reparative gene expression in monocytes early and remotely post-MI. Methods: Single-cell transcriptome data indicated that reparative genes were activated early and remotely in bone marrow and circulating monocytes before cardiac recruitment. Western blotting and immunofluorescence staining revealed increases in histone lactylation levels, including the previously identified histone H3K18 lactylation in monocyte-macrophages early post-MI. Through joint CUT&amp;Tag and RNA-sequencing analyses, we identified Lrg1, Vegf-a , and IL-10 as histone H3K18 lactylation target genes. The increased modification and expression levels of these target genes post-MI were verified by chromatin immunoprecipitation-qPCR and reverse transcription-qPCR. Results: We demonstrated that histone lactylation regulates the anti-inflammatory and pro-angiogenic dual activities of monocyte-macrophages by facilitating reparative gene transcription and confirmed that histone lactylation favors a reparative environment and improves cardiac function post-MI. Furthermore, we explored the potential positive role of monocyte histone lactylation in reperfused MI. Mechanistically, we provided new evidence that monocytes undergo metabolic reprogramming in the early stage of MI and demonstrated that dysregulated glycolysis and MCT1 (monocarboxylate transporter 1)-mediated lactate transport promote histone lactylation. Finally, we revealed the catalytic effect of IL (interleukin)-1β-dependent GCN5 (general control non-depressible 5) recruitment on histone H3K18 lactylation and elucidated its potential role as an upstream regulatory element in the regulation of monocyte histone lactylation and downstream reparative gene expression post-MI. Conclusions: Histone lactylation promotes early remote activation of the reparative transcriptional response in monocytes, which is essential for the establishment of immune homeostasis and timely activation of the cardiac repair process post-MI.
Persisting Platelet Activation and Hyperactivity in COVID-19 Survivors
Authors: Remy Martins-Gonçalves, Mariana M. Campos, Lohanna Palhinha, Isaclaudia G. Azevedo-Quintanilha, Mayara Abud Mendes, Jairo Ramos Temerozo, Júlia Toledo-Mendes, Paulo H. Rosado-de-Castro, Fernando A. Bozza, Rosana Souza Rodrigues, Eugenio D. Hottz, Patricia T. Bozza
Journal: Circulation Research (2022)
Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade
Authors: Camilla Schinner, Lifen Xu, Henriette Franz, Aude Zimmermann, Marie-Therès Wanuske, Maitreyi Rathod, Pauline Hanns, Florian Geier, Pawel Pelczar, Yan Liang, Vera Lorenz, Chiara Stüdle, Piotr I. Maly, Silke Kauferstein, Britt M. Beckmann, Farah Sheikh, Gabriela M. Kuster, Volker Spindler
Journal: Circulation (2022)

Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell-cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression.We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVβ6 antibody.The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent transforming growth factor-β signaling as driver of cardiac fibrosis. Blocking integrin-αVβ6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo.We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVβ6 and transforming growth factor-β signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.
Preclinical Study of a Biparatopic METxMET Antibody–Drug Conjugate, REGN5093-M114, Overcomes MET-driven Acquired Resistance to EGFR TKIs in EGFR-mutant NSCLC
Authors: Seung Yeon Oh, You Won Lee, Eun Ji Lee, Jae Hwan Kim, YoungJoon Park, Seong Gu Heo, Mi Ra Yu, Min Hee Hong, John DaSilva, Christopher Daly, Byoung Chul Cho, Sun Min Lim, Mi Ran Yun
Journal: Clinical Cancer Research (2022)

MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody-drug conjugate targeting MET in MET-driven patient-derived models.